TY - JOUR
T1 - The transcription factor NR4A3 controls CD103+ dendritic cell migration
AU - Park, Kiwon
AU - Mikulski, Zbigniew
AU - Seo, Goo Young
AU - Andreyev, Aleksander Y.
AU - Marcovecchio, Paola
AU - Blatchley, Amy
AU - Kronenberg, Mitchell
AU - Hedrick, Catherine C.
N1 - Funding Information:
This work was supported by grants from the NIH (R01 HL134236, R01 HL118765, R01 HL097368, and P01 HL055798, to CCH, and F31 HL132538, to PM); the American Heart Association (fellowship grant 13POST17100127, to KP); and the National Research Foundation of Korea (NRF-2013 R1A1A2057931, to GS).
PY - 2016/12/1
Y1 - 2016/12/1
N2 - The transcription factor NR4A3 (also known as NOR-1) is a member of the Nr4a family of nuclear receptors and is expressed in myeloid and lymphoid cells. Here, we have shown that Nr4a3 is essential for the migration of CD103+ dendritic cells (DCs) to lymph nodes (LNs). Nr4a3-deficient mice had very few CD103+ migratory DCs (mDCs) present in LNs, and mixed-chimera studies revealed that this migratory defect was cell intrinsic. We further found that CD103+ DCs from Nr4a3-deficient mice displayed a marked loss of surface expression of the chemokine CCR7. This defect in CCR7 expression was confined to CD103+ DCs, as CCR7 expression on T lymphocytes was unaffected. Moreover, CCR7 was not induced on CD103+ DCs from Nr4a3-deficient mice in response to either administration of the TLR7 agonist R848 or infection with Citrobacter rodentium in vivo. The transcription factor FOXO1 has been shown to regulate CCR7 expression. We found that FOXO1 protein was reduced in Nr4a3-deficient DCs through an AKT-dependent mechanism. Further, we found a requirement for NR4A3 in the maintenance of homeostatic mitochondrial function in CD103+ DCs, although this is likely independent of the NR4A3/FOXO1/CCR7 axis in the regulation of DC migration. Thus, NR4A3 plays an important role in the regulation of CD103+ mDCs by regulating CCR7-dependent cell migration.
AB - The transcription factor NR4A3 (also known as NOR-1) is a member of the Nr4a family of nuclear receptors and is expressed in myeloid and lymphoid cells. Here, we have shown that Nr4a3 is essential for the migration of CD103+ dendritic cells (DCs) to lymph nodes (LNs). Nr4a3-deficient mice had very few CD103+ migratory DCs (mDCs) present in LNs, and mixed-chimera studies revealed that this migratory defect was cell intrinsic. We further found that CD103+ DCs from Nr4a3-deficient mice displayed a marked loss of surface expression of the chemokine CCR7. This defect in CCR7 expression was confined to CD103+ DCs, as CCR7 expression on T lymphocytes was unaffected. Moreover, CCR7 was not induced on CD103+ DCs from Nr4a3-deficient mice in response to either administration of the TLR7 agonist R848 or infection with Citrobacter rodentium in vivo. The transcription factor FOXO1 has been shown to regulate CCR7 expression. We found that FOXO1 protein was reduced in Nr4a3-deficient DCs through an AKT-dependent mechanism. Further, we found a requirement for NR4A3 in the maintenance of homeostatic mitochondrial function in CD103+ DCs, although this is likely independent of the NR4A3/FOXO1/CCR7 axis in the regulation of DC migration. Thus, NR4A3 plays an important role in the regulation of CD103+ mDCs by regulating CCR7-dependent cell migration.
UR - http://www.scopus.com/inward/record.url?scp=85002728338&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85002728338&partnerID=8YFLogxK
U2 - 10.1172/JCI87081
DO - 10.1172/JCI87081
M3 - Article
C2 - 27820700
AN - SCOPUS:85002728338
SN - 0021-9738
VL - 126
SP - 4603
EP - 4615
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -